IV Guideline
1 Introduction
1.1 Epidemiology, classification, staging
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Consensus-based statement 1.S1
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Expert consensus
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Level of consensus +++
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(Homologous) uterine sarcomas are a heterogeneous group of generally rare malignancies
(1.5 – 3/100 000) of the uterine muscles, endometrial stroma or uterine connective
tissue.
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Consensus-based recommendation 1.E1
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Expert consensus
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Level of consensus +++
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References: [1], [2]
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The terminology and morphological diagnosis of uterine sarcomas must be based on the
most current edition of the WHO classification.
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Consensus-based recommendation 1.E2
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Expert consensus
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Level of consensus +++
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Reference: [2]
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The postoperative staging of uterine sarcomas must be based on the most current edition
of the pTNM classification.
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The WHO classification lists the following entities as malignant mesenchymal tumors
or malignant mixed epithelial-mesenchymal tumors [2], [3]:
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leiomyosarcoma (LMS),
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low-grade endometrial stromal sarcoma (LG-ESS),
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high-grade endometrial stromal sarcoma (HG-ESS),
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undifferentiated uterine sarcoma (UUS),
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adenosarcoma (AS),
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PECome (perivascular epithelioid cell tumor), malignant variant.
The diagnosis of other extremely rare uterine sarcomas (e.g., heterologous sarcomas
such as rhabdomyosarcoma) must be based on the WHO classification of soft tissue sarcomas
[4].
This guideline considers the more common entities (LMS, LG-ESS, HG-ESS and UUS or
AS, including rhabdomyosarcoma of the uterus in children and adolescents) to the exclusion
of the
extremely rare forms (rhabdomyosarcoma in adulthood, angiosarcoma, osteosarcoma,
chondrosarcoma, liposarcoma, myxofibrosarcoma, alveolar soft tissue sarcoma and epithelioid
sarcoma).
The mean patient age at onset of disease is between 50 and 70 years, depending on
the tumor type. Identified risk factors include tamoxifen therapy. The incidence of
uterine sarcomas is 2
to 3 times higher in women of African descent compared to Asian women or women
of European descent.
The staging of uterine sarcomas must be done in accordance with the most current edition
of the pTNM classification. Inclusion of the FIGO stage is optional ([Tables 5] and [6]).
Tab. 5 FIGO and TNM stages for leiomyosarcomas and endometrial stromal sarcomas* of the
uterus.
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FIGO/TNM stage
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Definition
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* Tumors simultaneously present in the corpus uteri and the ovary/pelvis accompanied
by ovarian/pelvic endometriosis must be classified as independent primary tumors.
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I/T1
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Tumor limited to the uterus
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IA/T1a
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Tumor ≤ 5 cm in greatest dimension
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IB/T1b
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Tumor > 5 cm in greatest dimension
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II/T2
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Tumor extends beyond the uterus, within the pelvis
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IIA/T2a
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Involvement of the adnexa (unilateral or bilateral)
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IIB/T2b
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Tumor has spread to extrauterine pelvic tissue excluding the adnexa
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III/T3
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Tumor has infiltrated abdominal tissue
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N1
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IIIA/T3a
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One site
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IIIB/T3b
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More than one site
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IIIC
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Metastasis of pelvic and/or paraaortic lymph nodes
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IV/T4
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IVA/T4
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Tumor has infiltrated bladder and/or rectum
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IVB
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Distant metastasis
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Tab. 6 FIGO/TNM stages for adenosarcomas* of the uterus.
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FIGO-/TNM stage
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Definition
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* Tumors simultaneously present in the corpus uteri and the ovary/pelvis accompanied
by ovarian/pelvic endometriosis must be classified as independent primary tumors.
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I/T1
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Tumor limited to the uterus
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IA/T1a
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Tumor limited to the endometrium/endocervix without myometrial Infiltration
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IB/T1b
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Tumor has infiltrated less than half of the myometrium
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IC/T1c
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Tumor has infiltrated ≥ 50% of the myometrium
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II/T2
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Tumor has spread to the pelvis
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IIA/T2a
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Involvement of the adnexa (unilateral or bilateral)
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IIB/T2b
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Tumor has spread to extrauterine pelvic tissue excluding the adnexa
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III/T3
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Intraabdominal tumor spread
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N1
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IIIA/T3a
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One site
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IIIB/T3b
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More than one site
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IIIC
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Metastasis in pelvic and/or paraaortic lymph nodes
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IV/T4
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IVA/T4
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Tumor has infiltrated bladder and/or rectal mucosa
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IVB
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Distant metastasis
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1.2 Symptoms, general diagnostic workup (including imaging), general pathology
1.2.1 Symptoms
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Consensus-based statement 1.S2
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Expert consensus
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Level of consensus +++
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Uterine sarcomas are not associated with any specific symptoms.
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Suspicious symptoms generally include a “rapidly growing uterus” or a fast growing
“leiomyoma”, particularly in the post-menopausal period. This criterion has been described
several
times in the literature [5], [6], [7], [8]. The problem with
this, however, is that there is no valid definition of what constitutes “rapid
growth” nor has any relevant data been published which would allow clinically relevant
evaluation of this
parameter in terms of being able to differentiate between myoma and sarcoma.
If there is a clinical suspicion of uterine malignancy, morcellating procedures are
contraindicated, even after normal curettage, as they worsen the prognosis [9]. If morcellation is planned, patients must be informed in every case about the risk
and must be offered alternative procedures, even cases with tumors which appear to
be
clinically unsuspicious.
1.2.2 Imaging
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Consensus-based recommendation 1.E3
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Expert consensus
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Level of consensus +++
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Because of the high potential for metastasis, histologically confirmed uterine sarcoma
should be investigated further, and investigation should include imaging (CT/MRI)
of the
thorax and abdomen.
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Consensus-based statement 1.S3
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Expert consensus
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Level of consensus ++
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Imaging procedures such as sonography and MRI may yield information pointing to the
presence of a sarcoma but they are unable to exclude uterine sarcoma.
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No imaging procedure (sonography, CT, MRI, PET-CT) has any specific or reliable criteria
for detecting sarcomas [10].
As transvaginal sonography is typically used during normal uterine gynecological examinations,
it is the primary diagnostic imaging procedure used to evaluate the uterus.
Indicative changes have also been reported for imaging with MRI which partially correlate
with sonographic findings.
Abdominal CT is not suitable to evaluate the primary tumor; it is mainly used for
staging or to detect metastasis.
In this context, if the sarcoma has been confirmed, the patient should also always
be examined using thoracic CT, which can then serve as the basis for current management
of the lesion
with the findings used for follow-up.
1.2.3 General pathology
1.2.3.1 Specimens after hysterectomy or surgical therapy of uterine sarcomas
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Consensus-based recommendation 1.E4
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Expert consensus
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Level of consensus +++
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References: [2], [11], [12], [13]
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The morphological workup must include procedures which can gather all of the information
listed below.
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Grading of the histological tumor type based on the WHO classification
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Grading of ESS (low-grade or high-grade)
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Evidence for/no evidence of lymph node or blood vessel infiltration (L and V status)
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Evidence for/no evidence of perineural infiltration (PNI status)
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Staging (pTNM)
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Infiltration depth into the myometrium or (endo-)cervical stroma
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Three-dimensional tumor size, in cm
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Metric data about the minimal distance between the sarcoma and the respective relevant
resection margins
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R classification (UICC)
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Estrogen and progesterone receptor expression
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Consensus-based recommendation 1.E5
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Expert consensus
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Level of consensus +++
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As uterine sarcomas may be characterized by a high degree of intratumoral heterogeneity,
all tumors with a maximum diameter of ≤ 2 cm must be fully investigated. Tumors with
diameters > 2 cm must be embedded in paraffin, using one paraffin block
per centimeter of the greatest tumor dimension.
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Consensus-based recommendation 1.E6
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Expert consensus
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Level of consensus +++
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If the findings do not provide clear information about the malignancy or subtype,
a pathological examination must be carried out to investigate the tumor further.
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Consensus-based recommendation 1.E7
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Expert consensus
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Level of consensus +++
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All patients diagnosed with uterine sarcoma must be presented to an interdisciplinary
tumor conference.
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Consensus-based recommendation 1.E8
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Expert consensus
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Level of consensus ++
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The presentation must be carried out at a DKG-certified gynecological cancer center
or sarcoma center.
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1.3 Genetic predisposition
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Consensus-based recommendation 1.E9
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Expert consensus
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Level of consensus +++
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If the patient meets the criteria for germline analysis of the TP53 gene, the patient
must be offered genetic counselling with subsequent analysis to exclude a hereditary
tumor
syndrome.
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The overwhelming majority of sarcomas occur sporadically. Nevertheless, a diagnosis
of uterine sarcoma in childhood, adolescence or early adulthood can point to a hereditary
tumor
disposition syndrome, such as Li-Fraumeni syndrome (LFS) or TP53-associated
tumor syndrome [14], [15].
2 Uterine Leiomyosarcoma
2.1 Introduction, clinical symptoms and diagnostic workup
In Northern Europe, sarcomas occur in about 0.4 cases/100 000 women across all age
groups, with the highest incidence found in women between the ages of 45 and 59 years
[16].
The median age at onset of disease is 50 years [17].
Clinical symptoms reported by patients may include abnormal bleeding (e.g., mid-cycle
bleeding, postmenopausal bleeding) and, depending on the size of the lesion, a sensation
of pressure
in the vagina or abdomen. The results of curettage and/or endometrial biopsy,
e.g., in cases with postmenopausal bleeding, may be false-negative in around 50% of
cases and do not allow
leiomyosarcoma to be clearly excluded [6].
2.2 Histopathological diagnosis
Histologically, the WHO classification differentiates between classic (spindle cell)
leiomyosarcoma, an epithelioid and a myxoid variant [2].
[Table 7] provides a summary of the diagnostic criteria described in the current WHO classification
[2], [18], [19].
Tab. 7 Essential diagnostic criteria for uterine leiomyosarcomas [20], [21].
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HPF: high power field
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Conventional (spindle cell) LMS
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→
at least
2 criteria must be met
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moderate to high-grade cellular atypia (2+/3+ nuclear atypia)
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confirmed tumor cell necrosis
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> 4 mitoses/mm2 (corresponds to > 10 mitotic figures/10 hpf with a diameter of field of view of 0.55 mm
and a field-of-view surface of
0.24 mm2
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Epithelioid LMS
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→
at least
1 criterion must be met
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moderate to high-grade cellular atypia (2+/3+ nuclear atypia)
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confirmed tumor cell necrosis
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> 1.6 mitoses/mm2 (corresponds to > 4 mitotic figures/10 hpf with a diameter of field of view of 0.55 mm
and a field-of-view surface of
0.24 mm2
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Myxoid LMS
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→
at least
1 criterion must be met
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moderate to high-grade cellular atypia (2+/3+ nuclear atypia)
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confirmed tumor cell necrosis
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> 0.4 mitoses/mm2 (corresponds to > 1 mitotic figure/10 hpf with a diameter of field of view of 0.55 mm
and a field-of-view surface of
0.24 mm2
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infiltrative tumor borders or irregular lesion border
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2.3 Prognosis
LMS is a highly aggressive tumor with an unfavorable prognosis. The recurrence rates
range from 53 to 71% and the mean 5-year survival rate is between 40 and 50% [22], [23].
Additional prognostic factors include patient age, tumor resection margins, mitotic
index and vascular invasion [22], [24].
The most important iatrogenic negative prognostic factor is tumor injury, for
example, caused by morcellation, perforation and/or “myomectomy” [25].
2.4 Surgical treatment
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Consensus-based recommendation 2.E10
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Expert consensus
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Level of consensus ++
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If the sarcoma is limited to the uterus, the uterus must be completely resected without
morcellation or injury to the uterus.
The ovaries should be retained if the patient is premenopausal. The ovaries may be
retained in postmenopausal patients.
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Consensus-based recommendation 2.E11
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Expert consensus
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Level of consensus +++
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Systematic pelvic and paraaortic lymphadenectomy should not be carried out if the
lymph nodes are diagnostically unremarkable.
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Complete hysterectomy is the gold standard for the surgical management of leiomyosarcoma
limited to the uterus. There are no data which suggest that resection of the adnexa
could result
in a better prognosis. Therefore, resection of the adnexa should especially
not be carried out in premenopausal patients. The adnexa may also be retained in postmenopausal
patients; under
no circumstances should a second surgical intervention be carried out if the
adnexa were retained during the primary intervention [24], [26], [27]. Ovarian metastasis is rare, with an incidence of just 3%, and occurs almost exclusively
in cases with
intraperitoneal spread [27].
Irrespectively of the above, the option of an opportunistic salpingectomy should be
discussed with the patient in the context of discussing the primary intervention.
The incidence of primary pelvic and paraaortic lymph node metastasis is low in cases
with leiomyosarcoma. If lymph node involvement is present (often already detected
intraoperatively),
then extrauterine or hematogenic metastasis is usually already present. This
means that systematic pelvic and paraaortic lymphadenectomy will not be associated
with a better prognosis and
it is generally not recommended [26], [28], [29].
2.5 Adjuvant systemic therapy and radiotherapy
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Consensus-based recommendation 2.E12
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Expert consensus
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Level of consensus ++
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Adjuvant chemotherapy should generally not be administered to treat leiomyosarcoma.
Depending on the presence of other risk factors (e.g., higher tumor stage), adjuvant
chemotherapy may be administered in individual cases.
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Consensus-based recommendation 2.E13
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Expert consensus
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Level of consensus +++
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Radiotherapy should not be carried out after complete resection of a stage I/II leiomyosarcoma.
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Adjuvant systemic therapy is not generally indicated as, up to now, no randomized
controlled study has been able to provide evidence for any benefit in terms of overall
survival. This was
also confirmed by a meta-analysis [30], [31].
A prospective randomized phase III study, which was unfortunately halted after the
inclusion of just 81 patients (53 × LMS, 9 × HG-ESS, and 19 stage I – III carcinosarcomas)
due to a lack
of recruitment, reported a significantly higher 3-year progression-free survival
(PFS) rate (55 vs. 41%) following the administration of polychemotherapy consisting
of
doxorubicin/ifosfamide/cisplatin in addition to radiotherapy, but this had no
effect on overall survival rates [32]. The heterogeneous patient cohort and
the lack of an observation arm has made it impossible to come to definitive
conclusions [32].
Another prospective study [33], which analyzed outcomes after the administration of a combination of gemcitabine
and docetaxel, provided some evidence for
potential effectiveness in an adjuvant setting. But because the study included
all stages (I – IV), this has significantly limited conclusions about tumors which
are limited to the
uterus.
A consecutive prospective one-arm phase II study by the same working group which investigated
tumors limited to only the uterus treated with gemcitabine plus docetaxel followed
by
doxorubicin showed a longer PFS (57% 3-year PFS) compared to historic controls
[34].
A phase III study which aimed to build on these data also had to be discontinued after
the inclusion of just 38 patients because of the difficulty in recruiting more participants
[35].
Based on these results, adjuvant chemotherapy to treat higher-stage disease may at
least be discussed in individual cases, even if it has not been possible to date to
show evidence for a
significant improvement in the overall survival rate.
A randomized study [36] reported that adjuvant radiotherapy of the pelvis with 50.4 Gy in cases with stage
I or II disease resulted in better local control
in the overall patient collective with different sarcoma entities, but no effect
on the rate of local recurrence (20% with radiotherapy or 24% without radiotherapy)
or on the overall
survival was detected in the subgroup of patients with leiomyosarcoma (n = 99).
This means that radiotherapy is not generally indicated following complete resection
of a stage I/II
leiomyosarcoma. Radiotherapy can be considered in cases with R1/2 resection
and locally advanced disease if the tumor is limited to the pelvis. However, there
are no valid studies showing
a significant verifiable effect on overall survival.
2.6 Therapy for metastasis and recurrence
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Consensus-based recommendation 2.E4
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Expert consensus
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Level of consensus +++
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In cases with recurrence and/or metastasis of a LMS, maximum surgical cytoreduction
should be considered to achieve tumor clearance.
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Consensus-based recommendation 2.E5
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Expert consensus
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Level of consensus +++
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If the diagnosis is metastasized leiomyosarcoma, the first-line therapy must consist
of doxorubicin.
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There are some indications that complete surgical resection in cases of recurrence
of metastasis of uterine leiomyosarcoma is associated with a better prognosis compared
to chemotherapy
alone and/or radiotherapy [37] – [40]. Two studies carried out in a selected patient cohort reported better survival (median
survival 45 vs. 31 months or 2.0 vs. 1.1 years) after complete resection of
metastases in patients with leiomyosarcoma [37], [41]. The resection, particularly of individual lung and/or liver metastases, could prolong
survival in selected patients [42], [43], [44].
Palliative systemic therapy is indicated for patients with diffuse metastasis and
recurrence/metastasis which cannot be (can no longer be) treated with surgery. Such
a therapy should be
discussed in detail with the patient and the associated toxicity should be carefully
considered.
There are only a few substances such as ifosfamide, gemcitabine or doxorubicin that
are effective for mono-chemotherapy, and they have moderate response rates (partial
or complete
remission) of between 17% and 25% [45], [46].
Paclitaxel, cisplatin, topotecan and etoposide are not very effective and have low
response rates of less than 10% [47], [48], [49], [50].
In contrast, combination chemotherapies have higher response rates compared to monotherapies
but they are also associated with a higher toxicity [51], [52], [53].
Only one prospective randomized phase II trial has shown that combination therapy
is superior to mono-chemotherapy in terms of survival; therapy consisted of a combination
of
docetaxel/gemcitabine and was compared to monotherapy with gemcitabine [54]. However, another study with a comparable study design was unable to replicate
the results, so that ultimately it is still not clear whether this combination
offers a benefit for patients [55].
According to more recent data from a phase III study, a combination of docetaxel and
gemcitabine offered no benefit compared to monotherapy with doxorubicin to either
the overall patient
population with soft-tissue sarcomas or to the subgroup with uterine LMS (median
overall survival 67 vs. 76 weeks, HR 1.14, 95% CI 0.83 – 1.57; p = 0.41 for the overall
patient population,
n = 257) [56].
The use of trabectedin for second-line chemotherapy in a metastatic setting following
the administration of anthracyclines has been studied in phase II trials and should
be the drug of
choice for this indication. Although the rate of remission is low, stabilization
of disease was achieved in up to 50% of cases [57].
Pazopanib, a multiple tyrosine kinase inhibitor, is a further second-line therapy
option which has been investigated in a double-blind placebo-controlled phase III
study, although
patients with sarcoma types with varying histologies were included in the study.
As regards the rate of remission and the percentage of patients who experienced stabilization
of disease,
the same statement applies to pazopanib as for trabectedin. In the study, pazopanib
significantly increased the progression-free survival interval in both the overall
patient population
and in the subgroup of patients with LMS [58].
3 Low-grade Endometrial Stromal Sarcomas
3.1 Introduction, clinical symptoms, diagnostic workup
The median age at onset of disease is the 6th decade of life [17].
These tumors typically manifest as mid-cycle or postmenopausal bleeding, sometimes
accompanied by an enlarged uterus and the corresponding symptoms.
The WHO classification differentiates malignant endometrial stromal tumors into
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low-grade endometrial stromal sarcomas,
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high-grade endometrial stromal sarcomas, and
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undifferentiated uterine sarcomas [59].
3.2 Prognosis
The general prognosis for LG-ESS is favorable but depends on the initial tumor stage
at diagnosis [60]. The disease-specific 5-year survival rate for
low-grade ESS ís 80 – 90% and the 10-year survival rate is around 70% [61], [62]. If the tumor is limited to the uterus at
the time of diagnosis (stage I), the rates are 100% and 90%, respectively. The
survival rate decreases to around 40% for higher stage disease [29].
Positive hormone receptors are a favorable prognostic factor with regard to overall
survival [63].
3.3 Surgical treatment
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Consensus-based recommendation 3.E6
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Expert consensus
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Level of consensus ++
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In cases which are suspicious for sarcoma limited to the uterus, treatment must consist
of complete resection of the uterus without morcellation or injury to the uterus.
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Consensus-based recommendation 3.E7
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Expert consensus
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Level of consensus +++
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Reference: [64]
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There are no data available about the oncological safety of using hormone replacement
therapy after primary treatment of a low-grade ESS. Because of the tumor biology of
low-grade ESS and its high estrogen dependency, hormone replacement therapy
should not be recommended.
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Consensus-based recommendation 3.E8
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Expert consensus
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Level of consensus +++
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Systematic pelvic and paraaortic lymphadenectomy should not be carried out in cases
with diagnostically unremarkable lymph nodes.
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The therapy of choice is complete hysterectomy without injury to the uterus or morcellation
[65].
There is a lot of evidence about the endocrine dependence of LG-ESS and the pronounced
expression of hormone receptors. The question arises in this context, particularly
in premenopausal
patients, whether bilateral removal of the adnexa should also be carried out.
A retrospective analysis of 153 LG-ESS patients reported a significantly higher rate
of recurrence when the
ovaries were retained in premenopausal patients. But the analysis did not differentiate
between cases with complete resection of the tumor and cases with incomplete resection.
Moreover,
neither this analysis nor two further evaluations of the SEER database found
that leaving both adnexa in situ had a negative effect on overall survival. A meta-analysis
of 17 studies with
a total of 786 patients came to the same conclusion [66]. The benefits of ovarian preservation in younger patients should therefore be carefully
weighed
against the risk of a higher probability of recurrence and critically discussed
with affected patients [67], [68], [69].
Lymph node involvement is rare and does not appear to have an effect on prognosis.
Systematic lymphadenectomy and any adjuvant therapy options based on systematic lymphadenectomy
are
therefore not expected to extend survival, meaning that lymphadenectomy cannot
be routinely recommended [10], [62], [69], [70].
3.4 Adjuvant systemic therapy and radiotherapy
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Consensus-based recommendation 3.E9
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Expert consensus
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Level of consensus +++
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Adjuvant endocrine therapy should not generally be carried out for low-grade ESS but
may be administered in individual cases, depending on the presence of other risk factors
(e.g., higher tumor stage).
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Consensus-based recommendation 3.E10
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Expert consensus
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Level of consensus +++
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Adjuvant chemotherapy must not be administered.
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Consensus-based recommendation 3.E11
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Expert consensus
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Level of consensus +++
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Adjuvant radiotherapy must not be carried out.
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Postoperative adjuvant endocrine therapy may be discussed with patients with higher
tumor stages or after accidental morcellation, although prospective studies are lacking.
A
meta-analysis came to the conclusion that postoperative adjuvant endocrine therapy
results in a significantly lower risk of recurrence but it has no effect on the overall
survival. But the
validity of these results is limited by the heterogeneity of the patient population
without or with postoperative residual tumor [71]. The data from
comparative retrospective analyses of adjuvant therapy support the use of either
medroxyprogesterone acetate 200 mg/day (in Germany only available as 250 mg doses)
or megestrol acetate
80 – 160 mg/day or, alternatively, an aromatase inhibitor (letrozole 2.5 mg/day,
anastrozole 1 mg/day or exemestane 25 mg/day). The prerequisite for this is confirmed
adequate expression
of hormone receptors. The duration of adjuvant therapy has not been sufficiently
studied. A duration of 5 years is currently being discussed [72], [73], [74].
There are no valid data available for adjuvant chemotherapy.
A first SEER analysis of 3650 patients with uterine sarcomas found that percutaneous
pelvic radiotherapy (± brachytherapy) had a significant positive effect on the rate
of local
recurrence for both the total patient population [75] and for the subgroups of patients with ESS (n = 361: 97% vs. 93% after 5 years or
97% vs. 87% after 8
years) but had no impact on overall survival. A specific SEER analysis of 1010
patients with ESS was also unable to confirm that adjuvant radiotherapy had a significant
benefit on overall
survival [62]. The only randomized study on pelvic radiation for uterine sarcoma [36] which included 30 patients with
endometrial stromal sarcoma did not carry out a separate survival analysis for
this subgroup. Because of the unclear data and the medium and long-term side effects
of adjuvant radiotherapy
when loco-regional control is already good, adjuvant radiotherapy is not indicated.
3.5 Therapy for metastasis and recurrence
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Consensus-based recommendation 3.E12
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Expert consensus
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Level of consensus +++
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Maximum surgical cytoreduction may be considered in cases with recurrence and/or metastasis
to achieve tumor clearance.
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Consensus-based recommendation 3.E23
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Expert consensus
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Level of consensus +++
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Tamoxifen is contraindicated for LG-ESS.
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LG-ESS usually has a significantly better prognosis than LMS. However, recurrence
is possible even after several decades [76]. In every case of recurrence
or metastasis it is important to check whether surgery with the aim of complete
macroscopic resection is possible [77]. Because of their slow growth,
repeated resections of a low-grade endometrial stromal sarcoma may offer a benefit
[10].
After surgical resection, the option of anti-endocrine therapy should be discussed
with the patient. The prerequisite for this therapy is confirmed adequate expression
of hormone
receptors.
Anti-endocrine therapy should be recommended to all patients with postoperative residual
tumor, inoperable recurrence or multiple distant metastasis. Because of the high expression
of
estrogen and progesterone receptors, progestogens or aromatase inhibitors are
used for treatment [78], [79], [80], [81].
Retrospective analyses of small cases series indicated that medroxyprogesterone acetate
200 mg/day (available in Germany as 250 mg doses) or megestrol acetate 160 mg/day
are effective.
Response rates of up to 82% have been reported [79]. Alternatively, although less data are available, aromatase inhibitors (letrozole
2.5 mg/day,
anastrozole 1 mg/day or exemestane 25 mg/day) also appear to exert a positive
effect (60% remission and 40% stable disease after a median follow-up of 4 years)
(in Germany this is an
off-label use) [73], [80].
Because it is a risk factor for uterine sarcoma, tamoxifen must not be used for endocrine
therapy [82]. Any ongoing tamoxifen therapy must be discontinued,
and if tamoxifen is indicated for breast cancer, it must be replaced by an aromatase
inhibitor.
Targeted percutaneous radiotherapy may be used as palliative therapy for recurrence/metastasis
which cannot be completely resected [83], [84].
4 High-grade Endometrial Stromal Sarcomas and Undifferentiated Uterine Sarcomas
4.1 Introduction, clinical symptoms and diagnostic workup
Although there are clear pathological anatomical differences between HG-ESS and UUS,
both entities share a number of similarities with regard to incidence, clinical presentation,
prognosis and even therapy, which is why they are discussed together here. The
staging corresponds to that used for LMS.
The median age at onset of disease is 60 years. The tumors typically manifest as pathological
bleeding, sometimes accompanied by an enlarged uterus and related symptoms. Because
of the
aggressiveness of the tumor, the diagnosis is often only made at an advanced
stage of disease.
4.2 Prognosis
As regards prognosis, the prognosis for HG-ESS is much closer to that of highly aggressive
undifferentiated uterine sarcomas (UUS) rather than the more favorable prognosis of
LG-ESS [85]. Studies have shown that a threshold value of > 25 mitotic figures in 10 hpf is
prognostically relevant [86], [87].
Because disease is often only detected at an advanced stage, the prognosis is generally
unfavorable with a median overall survival of 1 – 3 years [88], [89], [90].
4.3 Surgical treatment
|
Consensus-based recommendation 4.E24
|
|
Expert consensus
|
Level of consensus +++
|
|
If the sarcoma is limited to the uterus, the uterus must be completely resected without
morcellation or injury to the uterus.
The ovaries should be retained if the patient is premenopausal. The ovaries may be
retained in postmenopausal patients.
|
|
Consensus-based recommendation 4.E25
|
|
Expert consensus
|
Level of consensus +++
|
|
Systematic pelvic and paraaortic lymphadenectomy should not be carried out if the
lymph nodes are diagnostically unremarkable.
|
Complete hysterectomy (without morcellation or injury of the uterus) is the therapy
of choice. The benefit of bilateral adnexa resection has not been confirmed and is
questionable, given
the lack of hormone receptor expression in most HG-ESS. The adnexa may therefore
be retained in premenopausal patients.
Although positive pelvic and/or paraaortic lymph nodes are associated with a poorer
prognosis, according to an analysis of the SEER database, lymphadenectomy is not associated
with a
better survival [62].
4.4 Adjuvant systemic therapy and radiotherapy
|
Consensus-based recommendation 4.E26
|
|
Expert consensus
|
Level of consensus +++
|
|
Adjuvant chemotherapy should not be generally administered to patients with HG-ESS/UUS,
but may be administered in individual cases depending on the presence of additional
risk
factors (e.g., high tumor stage).
Radiotherapy should not be carried out after complete resection of HG-ESS/UUS.
|
There are no valid prospective data for adjuvant chemotherapy. However, multivariate
analysis carried out in a retrospective analysis of 39 patients in the French Sarcoma
Group showed
that chemotherapy was associated with a significant survival benefit [90]. This means that adjuvant chemotherapy may be discussed in individual cases,
particularly cases with advanced stage disease, but patients must be informed
about the related side effects and the lack of evidence confirming its efficacy.
The data on the benefit of adjuvant radiotherapy is limited and heterogeneous.
A multicenter retrospective analysis investigated 59 patients with endometrial stromal
tumors, 29 of whom had undifferentiated uterine sarcomas (58% with stage I or II disease
[91]). 86% of patients were given pelvic teletherapy (median dose for the overall patient
population was 48 Gy) and 51% had brachytherapy. The overall survival
rate of patients with undifferentiated uterine sarcomas was 65% at 5 years and
locoregional control was achieved in 40% of patients. Multivariate analysis found
that pelvic radiotherapy
was associated with a significantly better overall survival of the total patient
population (endometrial stromal sarcoma and undifferentiated uterine sarcoma).
A retrospective analysis of 39 patients in the French Sarcoma Group came to similar
conclusions [90].
In contrast, a detailed analysis of the SEER database found that postoperative radiotherapy
offered no survival benefit to patients (HG-ESS and LG-ESS, all stages of disease)
[62].
However, because of the heterogeneous patient cohorts, low case numbers and retrospective
nature of the studies, it is not possible to draw definitive conclusions.
4.5 Therapy for metastasis and recurrence
Chemotherapy for this tumor entity is analogous to that for LMS, although specific
data are limited.
There are some indications that certain recurrences are histologically heterogeneous
(displaying aspects of high and low-grade tumors) and that in tumors with evidence
of receptors,
endocrine therapy only affects the low-grade part, while the high-grade part
which determines prognosis is not affected by hormone therapy [92].
In contrast to LG-ESS, endocrine therapy does not play any role.
5 Uterine Adenosarcomas
5.1 Introduction, clinical symptoms and diagnostic workup
This rare entity occurs in all age groups [93] but peaks in the 6th and 7th decade of life. As adenosarcomas (AS) develop in the
endometrium, they often
take the form of polyps in the uterine cavity [94]. In the majority of cases, the symptoms of AS are therefore similar to those of
endometrial carcinomas
and consist of mid-cycle or postmenopausal bleeding, possibly accompanied by
an enlarged uterus and related symptoms. In contrast to most other uterine sarcomas,
AS present on imaging as
(polypoid) intracavitary tumors.
Because of its exposed location in the uterine cavity as described above, in the majority
of cases AS are correctly identified as malignancies during hysteroscopy/curettage
[95].
According to the WHO classification, adenosarcomas (AS) are defined as epithelial-mesenchymal
tumors with benign epithelial and malignant mesenchymal components [20], [79], [80], [96], [97]. In ~ 90% of cases, the
mesenchymal component has a low-grade histology. If the mesenchymal component
can be confirmed in more than 25% of the total tumor area or if there is a high-grade
sarcomatous component,
the diagnosis is AS with sarcomatous overgrowth (SO) [98], [99].
5.2 Prognosis
The recurrence rate for adenosarcoma without sarcomatous overgrowth is 15 – 25%, but
the recurrence rate for cases with sarcomatous overgrowth is 45 – 70%. A higher rate
of recurrence has
also been observed for deep myometrial invasion, lymph node invasion, highly
malignant heterologous stromal component and/or extrauterine spread. The mortality
rate for a typical
adenosarcoma is 10 – 25%, but it can be as high as 75% in cases with sarcomatous
overgrowth.
5.3 Surgical treatment
|
Consensus-based recommendation 4.E27
|
|
Expert consensus
|
Level of consensus +++
|
|
If the sarcoma is limited to the uterus, the uterus must be completely resected without
morcellation or injury to the uterus.
|
As with the other sarcomas, the treatment of choice consists of complete hysterectomy
without injury to the uterus or morcellation.
It is not clear whether the adnexa should also be removed. An analysis of the SEER
database (n = 162 patients with adenosarcomas) found that bilateral adnexa resection
had no impact on
survival [27].
The value of systematic pelvic and paraaortic lymphadenectomy is also not clear [72]. The probability of lymph node involvement is only 3 – 4% [100].
Because of this low incidence and the fact that lymph node status had no effect on
patient survival in this analysis, systematic lymphadenectomy is not routinely recommended.
5.4 Adjuvant systemic therapy and radiotherapy
To date, no benefit has been reported for any adjuvant therapy. Based on 1884 cases
in the National Cancer Database, chemotherapy has no effect on survival and postoperative
radiotherapy
even had a negative effect on survival [100].
As with other uterine sarcomas, neither adjuvant chemotherapy nor radiotherapy are
currently indicated after complete surgical resection.
If surgical resection was incomplete or in cases with advanced disease, treatment
in cases with sarcomatous overgrowth should be based on treatment for HG-ESS while
treatment in cases
without sarcomatous overgrowth and with confirmed expression of hormone receptors
should be similar to that for LG-ESS. As with LG-ESS, tamoxifen is contraindicated.
5.5 Therapy for metastasis and recurrence
It has been reported that complete surgical resection is associated with better survival
rates (26 vs. 15 months) in cases of recurrence or metastasis of AS [101].
Because of the above, as with other uterine sarcomas, it is recommended to check whether
surgery aiming for complete macroscopic resection is possible.
There is no optimal regimen for systemic therapy. Recurrence of adenosarcoma with
sarcomatous overgrowth should be treated with chemotherapy in the same way as HG-ESS
[102]. Recurrence of adenosarcoma without sarcomatous overgrowth but with hormone receptor
expression should be treated with endocrine therapy in the same way
as LG-ESS.
6 Rhabdomyosarcomas of the Uterus in Children and Adolescents
In childhood and adolescence, the predilection sites for rhabdomyosarcoma are the
vagina, cervix and uterus. Around 10% of all rhabdomyosarcomas detected in girls occur
in the female
genital tract. The median age at diagnosis is 1.9 years for vaginal, 2.7 years
for uterine and 13.5 years for cervical rhabdomyosarcomas. 97% of all rhabdomyosarcomas
of the female genital
tract present with non-alveolar histological findings. 5% of all patients have
regional lymph node involvement. Survival rates of children are very good (event-free
10-year survival: 74%;
10-year overall survival: 92%) [103], [104].
The presence of a mass in the vagina, cervix and/or uterus in a child or adolescent
is always suspicious for rhabdomyosarcoma. A biopsy must be carried out to confirm
the diagnosis in all
cases, and mutilating surgery should be avoided [103]. The required multimodal treatment should be carried out in a center for pediatric
oncology in
accordance with the guidelines of the Joint Federal Committee of Germany (Section
136 para. 1 sentence 1 no. 2, vol. V of the German Social Insurance Code [SGB V]).
The following diagnostic measures are recommended for staging: thoracic CT, ultrasound
or MRI of the abdomen and pelvis to obtain images of the efferent lymph nodes, bone
marrow biopsies
carried out at two different sites and a bone scan [105].
The initial risk stratification is based on the following clinical parameters ([Table 8]).
Tab. 8 Risk stratification based on clinical parameters for rhabdomyosarcomas.
|
Risk
|
Parameter
|
|
Low risk
|
Non-alveolar histology
|
|
Tumor diameter ≤ 5 cm and age at diagnosis < 10 years
|
|
N0, M0
|
|
primary R0 resection
|
|
Standard risk
|
Non-alveolar histology
|
|
N0, M0
|
|
primary R1/R2 resection
|
|
High risk
|
Non-alveolar histology and N1
|
|
Alveolar histology and N0
|
|
M0
|
|
Very high risk
|
Alveolar histology and N1
|
|
M0
|
|
Systematic metastasis
|
M1
|
After biopsy has confirmed the diagnosis, primary surgery should only be attempted
if organ-preserving R0 resection is possible. All other tumors must be treated with
neoadjuvant
polychemotherapy. The intensity of chemotherapy depends on the initial risk stratification
[103], [105].
The definitive local therapy should be carried out after 10 weeks of neoadjuvant chemotherapy.
Mutilating surgery should be avoided [103], [105].
If the initial surgery results in R0 resection, adjuvant radiotherapy is not indicated
in cases with non-alveolar tumors [103], [105]. Otherwise, adjuvant radiotherapy in the form of organ-preserving surgery combined
with brachytherapy carried out in specialized centers should be considered [103], [106].
All children and adolescents with rhabdomyosarcoma of the female genital tract should
receive adjuvant chemotherapy [103], [105]. The indication for adjuvant chemotherapy does not depend on when resection was
carried out or on the resection status. The intensity of chemotherapy depends on the
initial
risk stratification and the resection result [103], [105].
Maintenance chemotherapy is additionally recommended in cases with metastatic disease,
lymph node involvement and/or alveolar histology [6].
7 Follow-up
|
Consensus-based recommendation 7.E28
|
|
Expert consensus
|
Level of consensus +++
|
|
In the first 2 – 3 years after primary therapy, patients should have a regular follow-up
examination every three months with follow-up consisting of speculum examination,
vaginal
and rectal examination and, if necessary, ultrasound.
|
|
Consensus-based recommendation 7.E29
|
|
Expert consensus
|
Level of consensus +++
|
|
An additional diagnostic workup consisting of imaging for the early detection of metastasis
can be beneficial.
|
Follow-up serves to secure the success of treatment and preserve the patientʼs quality
of life.
It is not clear whether local intervention following the early detection of unilocular
recurrence/metastasis results in an improvement of overall survival.
Nevertheless, as part of the additional diagnostic workup for the early detection
of metastasis, imaging can be used as it may improve the chances of achieving complete
resection (cf. the
specific chapters on individual entities).
8 Morcellation
|
Consensus-based recommendation 8.E30
|
|
Expert consensus
|
Level of consensus +++
|
|
The use of morcellation techniques to treat uterine sarcomas results in a worse prognosis.
Patients must be informed of this.
|
|
Consensus-based recommendation 8.E31
|
|
Expert consensus
|
Level of consensus +++
|
|
Morcellation must not be carried out in a postmenopausal patient if the patient has
been diagnosed with a newly developed “myoma”, a large rapidly growing “myoma” or
a “myoma”
which has become symptomatic for the first time.
|
|
Consensus-based recommendation 8.E32
|
|
Expert consensus
|
Level of consensus +++
|
|
Contained in-bag morcellation cannot exclude the dissemination of tumor cells.
|
|
Consensus-based recommendation 8.E33
|
|
Expert consensus
|
Level of consensus +++
|
|
Patients who had a morcellation procedure to remove a uterine sarcoma must present
to a DKG-certified gynecological cancer center very soon after the morcellation procedure.
|
|
Consensus-based recommendation 8.E34
|
|
Expert consensus
|
Level of consensus +++
|
|
Systemic therapy should not generally be carried out after morcellation; nevertheless,
systemic therapy may be administered because of the higher risk of recurrence after
morcellation.
|
Irrespective of the surgical approach, morcellation of what is presumed to be benign
tissue can occur during uterus-preserving surgery to manage fibroid myomas or during
total or subtotal
hysterectomy procedures, and postoperative examination of the resected specimen
may reclassify it as a uterine sarcoma.
The prevalence of previously unknown uterine sarcomas detected during hysterectomy
or myoma procedures varies in the literature; it is reported to be between 1/204 and
1/7400
(0.49 – 0.014%). A summary analysis of the rate of accidentally operated uterine
sarcomas reported in 10 international studies with 8753 surgical procedures resulted
in an incidence of 0.24%
[107]. A meta-analysis of 10 120 patients from 9 studies reported a comparable incidence
for accidentally operated uterine sarcomas of 0.29% [108]. A German analysis published in 2017 of 475 morcellation procedures carried out
from 2004 to 2014 found a risk of 0.35% (1/280) for the accidental
morcellation of a previously unknown uterine sarcoma during hysterectomy and
no case of uterine sarcoma during 195 myoma morcellation procedures (0/195) [109]. Another German study of 10 731 LASH procedures reported a rate of 0.06% for uterine
sarcomas and 0.07% for endometrial carcinomas [110]. One
of the largest series with a total of 26 643 patients included 88 cases with
uterine sarcoma (prevalence 0.33%), of which 29 were LMS, 48 were ESS and 11 were
adenosarcomas [111].
Endoscopic intraabdominal morcellation of undetected sarcomas during hysterectomy
procedures, conservative surgical management of uterine myomas and laparoscopic supracervical
hysterectomy
(LASH) procedures are particularly associated with a worse oncological prognosis
in terms of recurrence-free survival and overall survival [5], [7], [107], [112], [113], [114], [115].
A systematic review of the literature and meta-analysis of 4 studies with 202 patients
(75 with and 127 without morcellation) published in 2015 reported a higher rate of
recurrence after
morcellation (62% versus 39%; odds ratio [OR] 3.16; 95% confidence interval [CI]
1.38 – 7.26) and a higher rate of intraabdominal recurrence (39% versus 9%; OR 4.11;
95% CI 1.92 – 8.81). The
overall survival rate after morcellation was also significantly lower (48% versus
29%; OR 2.42; 95% CI 1.19 – 4.92) [116]. However, there was no difference
in the rate of extra-abdominal recurrence. These data have been confirmed by
further studies [9], [117], [118], [119], [120] but not by all [121] – [124]. In a large retrospective series of 843 occult endometrial carcinomas and 334 occult
uterine sarcomas, the cancer-specific 5-year mortality after
hysterectomy with morcellation was significantly higher compared to procedures
without morcellation (hazard ratio [HR] 2.66; 95% CI 1.11 – 6.37) [111]. But
this association was limited to uterine sarcomas and was not found for endometrial
carcinomas.
Because of this increased risk of recurrence after morcellation, systemic therapy
may be administered even though there is no evidence that it can improve the prognosis
again.
Accidental morcellation during vaginal hysterectomy does not appear to increase the
risk of recurrence. Wasson et al. analyzed 2296 vaginal hysterectomies, with morcellation
carried out in
611 cases [125]. The incidence of accidentally morcellated malignancies was 0.82% (5/611); 3 cases
were endometrial carcinoma and 2 cases were sarcoma. No
recurrence was observed in any of the 5 cases. Another analysis of more than
3000 hysterectomies with a total of 18 sarcomas confirmed the observation that transvaginal
morcellation does not
increase the rate of recurrence [126]. It should be noted, however, that all of these studies were retrospective observational
studies.
It is not possible to definitively exclude uterine sarcoma preoperatively based on
clinical symptoms, growth patterns, ultrasound, CT, PET-CT or MRI [107], [127]. The risk score proposed by the International Society for Gynecologic Endoscopy
(ISGE) is only based on a summary of clinical and
ultrasound or MRI criteria taken from the literature [7]. The score has not yet been validated in a prospective patient population. The same
applies to the
rPRESS score developed by Zhang and colleagues [128], which is additionally based on very small number of cases [129].
Significantly higher case numbers (826 patients with leiomyomas or 293 patients
with LMS) were analyzed for the score developed by Köhler and colleagues [8].
However, their study only collected retrospective data for LMS, and no prospective
validation of the score has yet been done.
The use of these scores is therefore not recommended.
Caution is always warranted if risk factors are present: in addition to age, a generally
acknowledged risk factor for uterine sarcoma is ongoing or completed tamoxifen therapy
[130].
Hereditary tumor syndromes such as Li-Fraumeni syndrome (which is associated with
sarcoma), or Lynch syndrome and PTEN syndrome (which are associated with endometrial
carcinoma) are also
contraindications for morcellation [131].
The occurrence of sonographically visible or palpable uterine tumors in the postmenopausal
period is unphysiological as is increased growth of a known “myoma”. Although none
of these
factors have been confirmed, either in isolation or in combination, as risk factors
for uterine sarcoma, from a clinical and pathophysiological perspective, it may be
wise to assume that
such cases have an increased risk of uterine sarcoma.
The use of contained in-bag morcellation to prevent the dissemination of malignant
cells during morcellation surgery has been described in various studies [132], [133], [134], [135]. But contained in-bag morcellation has still not been
clinically validated, meaning that it is not possible to make a reliable statement
about the oncological safety of this technique [7], [107], [115]. A recent analysis of the Cochrane database published in 2020 found no evidence
that contained in-bag morcellation
for intracorporeal or extracorporeal morcellation is an effective or safe procedure
[136].
As regards the appropriate procedure after morcellation of a sarcoma, the choice of
approach should be guided by the statements in the position paper issued by the German
Society for
Gynecology and Obstetrics [107] and by international recommendations and statements [5], [7], [112], [113], [114], [115]. These statements
also apply to open or endoscopic tumor resections, irrespective of whether morcellation
is carried out or not [122]. The consensus is that the appropriate
oncological surgery recommended for the individual tumor entity should be carried
out as soon as possible. It has not been confirmed whether this approach affects overall
survival.
9 Information for patients
|
Consensus-based recommendation 9.E35
|
|
Expert consensus
|
Level of consensus +++
|
|
The patient must be offered the option to include her partner or family members in
talks and discussions.
|
|
Consensus-based recommendation 9.E36
|
|
Expert consensus
|
Level of consensus +++
|
|
The patient must be informed about the option of contacting self-help groups.
|
